1   404 184 ANALYSIS OF EPIGENETIC AGE PREDICTORS IN PAIN-RELATED CONDITIONS. CHRONIC PAIN PREVALENCE IS HIGH WORLDWIDE AND INCREASES AT OLDER AGES. SIGNS OF PREMATURE AGING HAVE BEEN ASSOCIATED WITH CHRONIC PAIN, BUT FEW STUDIES HAVE INVESTIGATED AGING BIOMARKERS IN PAIN-RELATED CONDITIONS. A SET OF DNA METHYLATION (DNAM)-BASED ESTIMATES OF AGE, CALLED "EPIGENETIC CLOCKS," HAS BEEN PROPOSED AS BIOLOGICAL MEASURES OF AGE-RELATED ADVERSE PROCESSES, MORBIDITY, AND MORTALITY. THE AIM OF THIS STUDY IS TO ASSESS IF DIFFERENT PAIN-RELATED PHENOTYPES SHOW ALTERATIONS IN DNAM AGE. IN OUR ANALYSIS, WE CONSIDERED THREE COHORTS FOR WHICH WHOLE-BLOOD DNAM DATA WERE AVAILABLE: HEAT PAIN SENSITIVITY (HPS), INCLUDING 20 MONOZYGOTIC TWIN PAIRS DISCORDANT FOR HEAT PAIN TEMPERATURE THRESHOLD; FIBROMYALGIA (FM), INCLUDING 24 CASES AND 20 CONTROLS; AND HEADACHE, INCLUDING 22 CHRONIC MIGRAINE AND MEDICATION OVERUSE HEADACHE PATIENTS (MOH), 18 EPISODIC MIGRAINEURS (EM), AND 13 HEALTHY SUBJECTS. WE USED THE HORVATH'S EPIGENETIC AGE CALCULATOR TO OBTAIN DNAM-BASED ESTIMATES OF EPIGENETIC AGE, TELOMERE LENGTH, LEVELS OF 7 PROTEINS IN PLASMA, NUMBER OF SMOKED PACKS OF CIGARETTES PER YEAR, AND BLOOD CELL COUNTS. WE DID NOT FIND DIFFERENCES IN EPIGENETIC AGE ACCELERATION, CALCULATED USING FIVE DIFFERENT EPIGENETIC CLOCKS, BETWEEN SUBJECTS DISCORDANT FOR PAIN-RELATED PHENOTYPES. TWINS WITH HIGH HPS HAD INCREASED CD8+ T CELL COUNTS (NOMINAL P = 0.028). HPS THRESHOLDS WERE NEGATIVELY ASSOCIATED WITH ESTIMATED LEVELS OF GDF15 (NOMINAL P = 0.008). FM PATIENTS SHOWED DECREASED NAIVE CD4+ T CELL COUNTS COMPARED WITH CONTROLS (NOMINAL P = 0.015). THE SEVERITY OF FM MANIFESTATIONS EXPRESSED THROUGH VARIOUS EVALUATION TESTS WAS ASSOCIATED WITH DECREASED LEVELS OF LEPTIN, SHORTER LENGTH OF TELOMERES, AND REDUCED CD8+ T AND NATURAL KILLER CELL COUNTS (NOMINAL P < 0.05), WHILE THE DURATION OF PAINFUL SYMPTOMS WAS POSITIVELY ASSOCIATED WITH TELOMERE LENGTH (NOMINAL P = 0.034). NO DIFFERENCES IN DNAM-BASED ESTIMATES WERE DETECTED FOR MOH OR EM COMPARED WITH CONTROLS. IN SUMMARY, OUR STUDY SUGGESTS THAT HPS, FM, AND MOH/EM DO NOT SHOW SIGNS OF EPIGENETIC AGE ACCELERATION IN WHOLE BLOOD, WHILE HPS AND FM ARE ASSOCIATED WITH DNAM-BASED ESTIMATES OF IMMUNOLOGICAL PARAMETERS, PLASMA PROTEINS, AND TELOMERE LENGTH. FUTURE STUDIES SHOULD EXTEND THESE OBSERVATIONS IN LARGER COHORTS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
2   173  50 ACCELERATED AGING IN BIPOLAR DISORDERS: AN EXPLORATORY STUDY OF SIX EPIGENETIC CLOCKS. BIPOLAR DISORDER (BD) IS A CHRONIC AND SEVERE PSYCHIATRIC DISORDER ASSOCIATED WITH SIGNIFICANT MEDICAL MORBIDITY AND REDUCED LIFE EXPECTANCY. IN THIS STUDY, WE ASSESSED ACCELERATED EPIGENETIC AGING IN INDIVIDUALS WITH BD USING VARIOUS DNA METHYLATION (DNAM)-BASED MARKERS. FOR THIS PURPOSE, WE USED FIVE EPIGENETIC CLOCKS (HORVATH, HANNUM, EN, PHENOAGE, AND GRIMAGE) AND A DNAM-BASED TELOMERE LENGTH CLOCK (DNAMTL). DNAM PROFILES WERE OBTAINED USING INFINIUM METHYLATIONEPIC ARRAYS FROM WHOLE-BLOOD SAMPLES OF 184 INDIVIDUALS WITH BD. WE ALSO ESTIMATED BLOOD CELL COUNTS BASED ON DNAM LEVELS FOR ADJUSTMENT. SIGNIFICANT CORRELATIONS BETWEEN CHRONOLOGICAL AGE AND EACH EPIGENETIC AGE ESTIMATED USING THE SIX DIFFERENT CLOCKS WERE OBSERVED. FOLLOWING ADJUSTMENT FOR BLOOD CELL COUNTS, WE FOUND THAT THE SIX EPIGENETIC AGEACCELS (AGE ACCELERATIONS) WERE SIGNIFICANTLY ASSOCIATED WITH THE BODY MASS INDEX. GRIMAGE AGEACCEL WAS SIGNIFICANTLY ASSOCIATED WITH MALE SEX, SMOKING STATUS AND CHILDHOOD MALTREATMENT. DNAMTL AGEACCEL WAS SIGNIFICANTLY ASSOCIATED WITH SMOKING STATUS. OVERALL, THIS STUDY SHOWED THAT DISTINCT EPIGENETIC CLOCKS ARE SENSITIVE TO DIFFERENT ASPECTS OF AGING PROCESS IN BD. FURTHER INVESTIGATIONS WITH COMPREHENSIVE EPIGENETIC CLOCK ANALYSES AND LARGE SAMPLES ARE REQUIRED TO CONFIRM OUR FINDINGS OF POTENTIAL DETERMINANTS OF AN ACCELERATED EPIGENETIC AGING IN BD.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
3  2624  33 EPIGENOME-WIDE ASSOCIATION STUDY (EWAS) OF BMI, BMI CHANGE AND WAIST CIRCUMFERENCE IN AFRICAN AMERICAN ADULTS IDENTIFIES MULTIPLE REPLICATED LOCI. OBESITY IS AN IMPORTANT COMPONENT OF THE PATHOPHYSIOLOGY OF CHRONIC DISEASES. IDENTIFYING EPIGENETIC MODIFICATIONS ASSOCIATED WITH ELEVATED ADIPOSITY, INCLUDING DNA METHYLATION VARIATION, MAY POINT TO GENOMIC PATHWAYS THAT ARE DYSREGULATED IN NUMEROUS CONDITIONS. THE ILLUMINA 450K BEAD CHIP ARRAY WAS USED TO ASSAY DNA METHYLATION IN LEUKOCYTE DNA OBTAINED FROM 2097 AFRICAN AMERICAN ADULTS IN THE ATHEROSCLEROSIS RISK IN COMMUNITIES (ARIC) STUDY. MIXED-EFFECTS REGRESSION MODELS WERE USED TO TEST THE ASSOCIATION OF METHYLATION BETA VALUE WITH CONCURRENT BODY MASS INDEX (BMI) AND WAIST CIRCUMFERENCE (WC), AND BMI CHANGE, ADJUSTING FOR BATCH EFFECTS AND POTENTIAL CONFOUNDERS. REPLICATION USING WHOLE-BLOOD DNA FROM 2377 WHITE ADULTS IN THE FRAMINGHAM HEART STUDY AND CD4+ T CELL DNA FROM 991 WHITES IN THE GENETICS OF LIPID LOWERING DRUGS AND DIET NETWORK STUDY WAS FOLLOWED BY TESTING USING ADIPOSE TISSUE DNA FROM 648 WOMEN IN THE MULTIPLE TISSUE HUMAN EXPRESSION RESOURCE COHORT. SEVENTY-SIX BMI-RELATED PROBES, 164 WC-RELATED PROBES AND 8 BMI CHANGE-RELATED PROBES PASSED THE THRESHOLD FOR SIGNIFICANCE IN ARIC (P < 1 X 10(-7); BONFERRONI), INCLUDING PROBES IN THE RECENTLY REPORTED HIF3A, CPT1A AND ABCG1 REGIONS. REPLICATION USING BLOOD DNA WAS ACHIEVED FOR 37 BMI PROBES AND 1 ADDITIONAL WC PROBE. SIXTEEN OF THESE ALSO REPLICATED IN ADIPOSE TISSUE, INCLUDING 15 NOVEL METHYLATION FINDINGS NEAR GENES INVOLVED IN LIPID METABOLISM, IMMUNE RESPONSE/CYTOKINE SIGNALING AND OTHER DIVERSE PATHWAYS, INCLUDING LGALS3BP, KDM2B, PBX1 AND BBS2, AMONG OTHERS. ADIPOSITY TRAITS ARE ASSOCIATED WITH DNA METHYLATION AT NUMEROUS CPG SITES THAT REPLICATE ACROSS STUDIES DESPITE VARIATION IN TISSUE TYPE, ETHNICITY AND ANALYTIC APPROACHES.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
4   308  35 ALCOHOL AND DNA METHYLATION: AN EPIGENOME-WIDE ASSOCIATION STUDY IN BLOOD AND NORMAL BREAST TISSUE. THE BIOLOGICAL MECHANISMS DRIVING ASSOCIATIONS BETWEEN ALCOHOL CONSUMPTION AND CHRONIC DISEASES MIGHT INCLUDE EPIGENETIC MODIFICATION OF DNA METHYLATION. WE EXPLORED THE HYPOTHESIS THAT ALCOHOL CONSUMPTION IS ASSOCIATED WITH METHYLATION IN AN EPIGENOME-WIDE ASSOCIATION STUDY OF BLOOD AND NORMAL BREAST TISSUE DNA. INFINIUM HUMANMETHYLATION450 BEADCHIP (ILLUMINA INC., SAN DIEGO, CALIFORNIA) ARRAY DATA ON BLOOD DNA METHYLATION WAS EXAMINED IN A DISCOVERY SET OF 2,878 NON-HISPANIC WHITE WOMEN FROM THE SISTER STUDY (UNITED STATES, 2004-2015) WHO PROVIDED DETAILED QUESTIONNAIRE INFORMATION ON LIFETIME ALCOHOL USE. ROBUST LINEAR REGRESSION MODELING WAS USED TO IDENTIFY SIGNIFICANT ASSOCIATIONS (FALSE DISCOVERY RATE OF Q < 0.05) BETWEEN THE NUMBER OF ALCOHOLIC DRINKS PER WEEK AND DNA METHYLATION AT 5,458 CYTOSINE-PHOSPHATE-GUANINE (CPG) SITES. ASSOCIATIONS WERE REPLICATED (P < 0.05) FOR 677 CPGS IN AN INDEPENDENT SET OF 187 BLOOD DNA SAMPLES FROM THE SISTER STUDY AND FOR 628 CPGS IN AN INDEPENDENT SET OF 171 NORMAL BREAST DNA SAMPLES; 1,207 CPGS WERE REPLICATED IN EITHER BLOOD OR NORMAL BREAST, WITH 98 CPGS REPLICATED IN BOTH TISSUES. INDIVIDUAL GENE EFFECTS WERE NOTABLE FOR PHOSPHOGLYCERATE DEHYDROGENASE (PGHDH), PEPTIDYL-PROLYL CIS-TRANS ISOMERASE (PPIF), SOLUTE CARRIER 15 (SLC15), SOLUTE CARRIER FAMILY 43 MEMBER 1 (SLC43A1), AND SOLUTE CARRIER FAMILY 7 MEMBER 11 (SLC7A11). WE ALSO FOUND THAT HIGH ALCOHOL CONSUMPTION WAS ASSOCIATED WITH SIGNIFICANTLY LOWER GLOBAL METHYLATION AS MEASURED BY THE AVERAGE OF CPGS ON THE ENTIRE ARRAY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
5  1436  35 DIFFERENTIAL METHYLATION OF THE TRPA1 PROMOTER IN PAIN SENSITIVITY. CHRONIC PAIN IS A GLOBAL PUBLIC HEALTH PROBLEM, BUT THE UNDERLYING MOLECULAR MECHANISMS ARE NOT FULLY UNDERSTOOD. HERE WE EXAMINE GENOME-WIDE DNA METHYLATION, FIRST IN 50 IDENTICAL TWINS DISCORDANT FOR HEAT PAIN SENSITIVITY AND THEN IN 50 FURTHER UNRELATED INDIVIDUALS. WHOLE-BLOOD DNA METHYLATION WAS CHARACTERIZED AT 5.2 MILLION LOCI BY MEDIP SEQUENCING AND ASSESSED LONGITUDINALLY TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS ASSOCIATED WITH HIGH OR LOW PAIN SENSITIVITY (PAIN DMRS). NINE META-ANALYSIS PAIN DMRS SHOW ROBUST EVIDENCE FOR ASSOCIATION (FALSE DISCOVERY RATE 5%) WITH THE STRONGEST SIGNAL IN THE PAIN GENE TRPA1 (P=1.2 X 10(-13)). SEVERAL PAIN DMRS SHOW LONGITUDINAL STABILITY CONSISTENT WITH SUSCEPTIBILITY EFFECTS, HAVE SIMILAR METHYLATION LEVELS IN THE BRAIN AND ALTERED EXPRESSION IN THE SKIN. OUR APPROACH IDENTIFIES EPIGENETIC CHANGES IN BOTH NOVEL AND ESTABLISHED CANDIDATE GENES THAT PROVIDE MOLECULAR INSIGHTS INTO PAIN AND MAY GENERALIZE TO OTHER COMPLEX TRAITS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
6  2643  34 EPIGENOMIC ASSOCIATION ANALYSIS IDENTIFIES SMOKING-RELATED DNA METHYLATION SITES IN AFRICAN AMERICANS. CIGARETTE SMOKING IS AN ENVIRONMENTAL RISK FACTOR FOR MANY CHRONIC DISEASES, AND DISEASE RISK CAN OFTEN BE MANAGED BY SMOKING CONTROL. SMOKING CAN INDUCE CELLULAR AND MOLECULAR CHANGES, INCLUDING EPIGENETIC MODIFICATION, BUT THE SHORT- AND LONG-TERM EPIGENETIC MODIFICATIONS CAUSED BY CIGARETTE SMOKING AT THE GENE LEVEL HAVE NOT BEEN WELL UNDERSTOOD. RECENT STUDIES HAVE IDENTIFIED SMOKING-RELATED DNA METHYLATION (DNAM) SITES IN CAUCASIANS. TO DETERMINE WHETHER THE SAME DNAM SITES ASSOCIATE WITH SMOKING IN AFRICAN AMERICANS, AND TO IDENTIFY NOVEL SMOKING-RELATED DNAM SITES, WE CONDUCTED A METHYLOME-WIDE ASSOCIATION STUDY OF CIGARETTE SMOKING USING A DISCOVERY SAMPLE OF 972 AFRICAN AMERICANS, AND A REPLICATION SAMPLE OF 239 AFRICAN AMERICANS WITH TWO ARRAY-BASED METHODS. AMONG 15 DNAM SITES SIGNIFICANTLY ASSOCIATED WITH SMOKING AFTER CORRECTION FOR MULTIPLE TESTING IN OUR DISCOVERY SAMPLE, 5 DNAM SITES ARE REPLICATED IN AN INDEPENDENT COHORT, AND 14 SITES IN THE REPLICATION SAMPLE HAVE EFFECTS IN THE SAME DIRECTION AS IN THE DISCOVERY SAMPLE. THE TOP TWO SMOKING-RELATED DNAM SITES IN F2RL3 (FACTOR II RECEPTOR-LIKE 3) AND GPR15 (G-PROTEIN-COUPLED RECEPTOR 15) OBSERVED IN AFRICAN AMERICANS ARE CONSISTENT WITH PREVIOUS FINDINGS IN CAUCASIANS. THE ASSOCIATIONS BETWEEN THE REPLICATED DNAM SITES AND SMOKING REMAIN SIGNIFICANT AFTER ADJUSTING FOR GENETIC BACKGROUND. DESPITE THE DISTINCT GENETIC BACKGROUND BETWEEN AFRICAN AMERICANS AND CAUCASIANS, THE DNAM FROM THE TWO ETHNIC GROUPS SHARES COMMON ASSOCIATIONS WITH CIGARETTE SMOKING, WHICH SUGGESTS A COMMON MOLECULAR MECHANISM OF EPIGENETIC MODIFICATION INFLUENCED BY ENVIRONMENTAL EXPOSURE.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
7   667  50 BLOOD-BASED EPIGENOME-WIDE ANALYSES OF 19 COMMON DISEASE STATES: A LONGITUDINAL, POPULATION-BASED LINKED COHORT STUDY OF 18,413 SCOTTISH INDIVIDUALS. BACKGROUND: DNA METHYLATION IS A DYNAMIC EPIGENETIC MECHANISM THAT OCCURS AT CYTOSINE-PHOSPHATE-GUANINE DINUCLEOTIDE (CPG) SITES. EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) INVESTIGATE THE STRENGTH OF ASSOCIATION BETWEEN METHYLATION AT INDIVIDUAL CPG SITES AND HEALTH OUTCOMES. ALTHOUGH BLOOD METHYLATION MAY ACT AS A PERIPHERAL MARKER OF COMMON DISEASE STATES, PREVIOUS EWAS HAVE TYPICALLY FOCUSED ONLY ON INDIVIDUAL CONDITIONS AND HAVE HAD LIMITED POWER TO DISCOVER DISEASE-ASSOCIATED LOCI. THIS STUDY EXAMINED THE ASSOCIATION OF BLOOD DNA METHYLATION WITH THE PREVALENCE OF 14 DISEASE STATES AND THE INCIDENCE OF 19 DISEASE STATES IN A SINGLE POPULATION OF OVER 18,000 SCOTTISH INDIVIDUALS. METHODS AND FINDINGS: DNA METHYLATION WAS ASSAYED AT 752,722 CPG SITES IN WHOLE-BLOOD SAMPLES FROM 18,413 VOLUNTEERS IN THE FAMILY-STRUCTURED, POPULATION-BASED COHORT STUDY GENERATION SCOTLAND (AGE RANGE 18 TO 99 YEARS). EWAS TESTED FOR CROSS-SECTIONAL ASSOCIATIONS BETWEEN BASELINE CPG METHYLATION AND 14 PREVALENT DISEASE STATES, AND FOR LONGITUDINAL ASSOCIATIONS BETWEEN BASELINE CPG METHYLATION AND 19 INCIDENT DISEASE STATES. PREVALENT CASES WERE SELF-REPORTED ON HEALTH QUESTIONNAIRES AT THE BASELINE. INCIDENT CASES WERE IDENTIFIED USING LINKAGE TO SCOTTISH PRIMARY (READ 2) AND SECONDARY (ICD-10) CARE RECORDS, AND THE CENSORING DATE WAS SET TO OCTOBER 2020. THE MEAN TIME-TO-DIAGNOSIS RANGED FROM 5.0 YEARS (FOR CHRONIC PAIN) TO 11.7 YEARS (FOR CORONAVIRUS DISEASE 2019 (COVID-19) HOSPITALISATION). THE 19 DISEASE STATES CONSIDERED IN THIS STUDY WERE SELECTED IF THEY WERE PRESENT ON THE WORLD HEALTH ORGANISATION'S 10 LEADING CAUSES OF DEATH AND DISEASE BURDEN OR INCLUDED IN BASELINE SELF-REPORT QUESTIONNAIRES. EWAS MODELS WERE ADJUSTED FOR AGE AT METHYLATION TYPING, SEX, ESTIMATED WHITE BLOOD CELL COMPOSITION, POPULATION STRUCTURE, AND 5 COMMON LIFESTYLE RISK FACTORS. A STRUCTURED LITERATURE REVIEW WAS ALSO CONDUCTED TO IDENTIFY EXISTING EWAS FOR ALL 19 DISEASE STATES TESTED. THE MEDLINE, EMBASE, WEB OF SCIENCE, AND PREPRINT SERVERS WERE SEARCHED TO RETRIEVE RELEVANT ARTICLES INDEXED AS OF MARCH 27, 2023. FIFTY-FOUR OF APPROXIMATELY 2,000 INDEXED ARTICLES MET OUR INCLUSION CRITERIA: ASSAYED BLOOD-BASED DNA METHYLATION, HAD >20 INDIVIDUALS IN EACH COMPARISON GROUP, AND EXAMINED ONE OF THE 19 CONDITIONS CONSIDERED. FIRST, WE ASSESSED WHETHER THE ASSOCIATIONS IDENTIFIED IN OUR STUDY WERE REPORTED IN PREVIOUS STUDIES. WE IDENTIFIED 69 ASSOCIATIONS BETWEEN CPGS AND THE PREVALENCE OF 4 CONDITIONS, OF WHICH 58 WERE NEWLY DESCRIBED. THE CONDITIONS WERE BREAST CANCER, CHRONIC KIDNEY DISEASE, ISCHEMIC HEART DISEASE, AND TYPE 2 DIABETES MELLITUS. WE ALSO UNCOVERED 64 CPGS THAT ASSOCIATED WITH THE INCIDENCE OF 2 DISEASE STATES (COPD AND TYPE 2 DIABETES), OF WHICH 56 WERE NOT REPORTED IN THE SURVEYED LITERATURE. SECOND, WE ASSESSED REPLICATION ACROSS EXISTING STUDIES, WHICH WAS DEFINED AS THE REPORTING OF AT LEAST 1 COMMON SITE IN >2 STUDIES THAT EXAMINED THE SAME CONDITION. ONLY 6/19 DISEASE STATES HAD EVIDENCE OF SUCH REPLICATION. THE LIMITATIONS OF THIS STUDY INCLUDE THE NONCONSIDERATION OF MEDICATION DATA AND A POTENTIAL LACK OF GENERALIZABILITY TO INDIVIDUALS THAT ARE NOT OF SCOTTISH AND EUROPEAN ANCESTRY. CONCLUSIONS: WE DISCOVERED OVER 100 ASSOCIATIONS BETWEEN BLOOD METHYLATION SITES AND COMMON DISEASE STATES, INDEPENDENTLY OF MAJOR CONFOUNDING RISK FACTORS, AND A NEED FOR GREATER STANDARDISATION AMONG EWAS ON HUMAN DISEASE.	2023	

8   382  43 AN EPIGENOME-WIDE STUDY OF BODY MASS INDEX AND DNA METHYLATION IN BLOOD USING PARTICIPANTS FROM THE SISTER STUDY COHORT. BACKGROUND/OBJECTIVES: THE RELATIONSHIP BETWEEN OBESITY AND CHRONIC DISEASE RISK IS WELL-ESTABLISHED; THE UNDERLYING BIOLOGICAL MECHANISMS DRIVING THIS RISK INCREASE MAY INCLUDE OBESITY-RELATED EPIGENETIC MODIFICATIONS. TO EXPLORE THIS HYPOTHESIS, WE CONDUCTED A GENOME-WIDE ANALYSIS OF DNA METHYLATION AND BODY MASS INDEX (BMI) USING DATA FROM A SUBSET OF WOMEN IN THE SISTER STUDY. SUBJECTS/METHODS: THE SISTER STUDY IS A COHORT OF 50 884 US WOMEN WHO HAD A SISTER WITH BREAST CANCER BUT WERE FREE OF BREAST CANCER THEMSELVES AT ENROLLMENT. STUDY PARTICIPANTS COMPLETED EXAMINATIONS WHICH INCLUDED MEASUREMENTS OF HEIGHT AND WEIGHT, AND PROVIDED BLOOD SAMPLES. BLOOD DNA METHYLATION DATA GENERATED WITH THE ILLUMINA INFINIUM HUMANMETHYLATION27 BEADCHIP ARRAY COVERING 27,589 CPG SITES WAS AVAILABLE FOR 871 WOMEN FROM A PRIOR STUDY OF BREAST CANCER AND DNA METHYLATION. TO IDENTIFY DIFFERENTIALLY METHYLATED CPG SITES ASSOCIATED WITH BMI, WE ANALYZED THIS METHYLATION DATA USING ROBUST LINEAR REGRESSION WITH ADJUSTMENT FOR AGE AND CASE STATUS. FOR THOSE CPGS PASSING THE FALSE DISCOVERY RATE SIGNIFICANCE LEVEL, WE EXAMINED THE ASSOCIATION IN A REPLICATION SET COMPRISED OF A NON-OVERLAPPING GROUP OF 187 WOMEN FROM THE SISTER STUDY WHO HAD DNA METHYLATION DATA GENERATED USING THE INFINIUM HUMANMETHYLATION450 BEADCHIP ARRAY. ANALYSIS OF THIS EXPANDED 450 K ARRAY IDENTIFIED ADDITIONAL BMI-ASSOCIATED SITES WHICH WERE INVESTIGATED WITH TARGETED PYROSEQUENCING. RESULTS: FOUR CPG SITES REACHED GENOME-WIDE SIGNIFICANCE (FALSE DISCOVERY RATE (FDR) Q<0.05) IN THE DISCOVERY SET AND ASSOCIATIONS FOR ALL FOUR WERE SIGNIFICANT AT STRICT BONFERRONI CORRECTION IN THE REPLICATION SET. AN ADDITIONAL 23 SITES PASSED FDR IN THE REPLICATION SET AND FIVE WERE REPLICATED BY PYROSEQUENCING IN THE DISCOVERY SET. SEVERAL OF THE GENES IDENTIFIED INCLUDING ANGPT4, RORC, SOCS3, FSD2, XYLT1, ABCG1, STK39, ASB2 AND CRHR2 HAVE BEEN LINKED TO OBESITY AND OBESITY-RELATED CHRONIC DISEASES. CONCLUSIONS: OUR FINDINGS SUPPORT THE HYPOTHESIS THAT OBESITY-RELATED EPIGENETIC DIFFERENCES ARE DETECTABLE IN BLOOD AND MAY BE RELATED TO RISK OF CHRONIC DISEASE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
9  2632  43 EPIGENOME-WIDE DNA METHYLATION AND PESTICIDE USE IN THE AGRICULTURAL LUNG HEALTH STUDY. BACKGROUND: PESTICIDE EXPOSURE IS ASSOCIATED WITH MANY LONG-TERM HEALTH OUTCOMES; THE POTENTIAL UNDERLYING MECHANISMS ARE NOT WELL ESTABLISHED FOR MOST ASSOCIATIONS. EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION, MAY CONTRIBUTE. INDIVIDUAL PESTICIDES MAY BE ASSOCIATED WITH SPECIFIC DNA METHYLATION PATTERNS BUT NO EPIGENOME-WIDE ASSOCIATION STUDY (EWAS) HAS EVALUATED METHYLATION IN RELATION TO INDIVIDUAL PESTICIDES. OBJECTIVES: WE CONDUCTED AN EWAS OF DNA METHYLATION IN RELATION TO SEVERAL PESTICIDE ACTIVE INGREDIENTS. METHODS: THE AGRICULTURAL LUNG HEALTH STUDY IS A CASE-CONTROL STUDY OF ASTHMA, NESTED WITHIN THE AGRICULTURAL HEALTH STUDY. WE ANALYZED BLOOD DNA METHYLATION MEASURED USING ILLUMINA'S EPIC ARRAY IN 1,170 MALE FARMERS OF EUROPEAN ANCESTRY. FOR PESTICIDES STILL ON THE MARKET AT BLOOD COLLECTION (2009-2013), WE EVALUATED NINE ACTIVE INGREDIENTS FOR WHICH AT LEAST 30 PARTICIPANTS REPORTED PAST AND CURRENT (WITHIN THE LAST 12 MONTHS) USE, AS WELL AS SEVEN BANNED ORGANOCHLORINES WITH AT LEAST 30 PARTICIPANTS REPORTING PAST USE. WE USED ROBUST LINEAR REGRESSION TO COMPARE METHYLATION AT INDIVIDUAL C-PHOSPHATE-G SITES (CPGS) AMONG USERS OF A SPECIFIC PESTICIDE TO NEVER USERS. RESULTS: USING FAMILY-WISE ERROR RATE (P < 9 X 10-8) OR FALSE-DISCOVERY RATE (FDR < 0.05), WE IDENTIFIED 162 DIFFERENTIALLY METHYLATED CPGS ACROSS 8 OF 9 CURRENTLY MARKETED ACTIVE INGREDIENTS (ACETOCHLOR, ATRAZINE, DICAMBA, GLYPHOSATE, MALATHION, METOLACHLOR, MESOTRIONE, AND PICLORAM) AND ONE BANNED ORGANOCHLORINE (HEPTACHLOR). DIFFERENTIALLY METHYLATED CPGS WERE UNIQUE TO EACH ACTIVE INGREDIENT, AND A DOSE-RESPONSE RELATIONSHIP WITH LIFETIME DAYS OF USE WAS OBSERVED FOR MOST. SIGNIFICANT CPGS WERE ENRICHED FOR TRANSCRIPTION MOTIFS AND 28% OF CPGS WERE ASSOCIATED WITH WHOLE BLOOD CIS-GENE EXPRESSION, SUPPORTING FUNCTIONAL EFFECTS OF FINDINGS. WE CORROBORATED A PREVIOUSLY REPORTED ASSOCIATION BETWEEN DICHLORODIPHENYLTRICHLOROETHANE (BANNED IN THE UNITED STATES IN 1972) AND EPIGENETIC AGE ACCELERATION. DISCUSSION: WE IDENTIFIED DIFFERENTIAL METHYLATION FOR SEVERAL ACTIVE INGREDIENTS IN MALE FARMERS OF EUROPEAN ANCESTRY. THESE MAY SERVE AS BIOMARKERS OF CHRONIC EXPOSURE AND COULD INFORM MECHANISMS OF LONG-TERM HEALTH OUTCOMES FROM PESTICIDE EXPOSURE. HTTPS://DOI.ORG/10.1289/EHP8928.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
10  1343  46 DETECTING CORD BLOOD CELL TYPE-SPECIFIC EPIGENETIC ASSOCIATIONS WITH GESTATIONAL DIABETES MELLITUS AND EARLY CHILDHOOD GROWTH. BACKGROUND: EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) HAVE PROVIDED OPPORTUNITIES TO UNDERSTAND THE ROLE OF EPIGENETIC MECHANISMS IN DEVELOPMENT AND PATHOPHYSIOLOGY OF MANY CHRONIC DISEASES. HOWEVER, AN IMPORTANT LIMITATION OF CONVENTIONAL EWAS IS THAT PROFILES OF EPIGENETIC VARIABILITY ARE OFTEN OBTAINED IN SAMPLES OF MIXED CELL TYPES. HERE, WE AIM TO ASSESS WHETHER CHANGES IN CORD BLOOD DNA METHYLATION (DNAM) ASSOCIATED WITH GESTATIONAL DIABETES MELLITUS (GDM) EXPOSURE AND EARLY CHILDHOOD GROWTH MARKERS OCCUR IN A CELL TYPE-SPECIFIC MANNER. RESULTS: WE ANALYZED 275 CORD BLOOD SAMPLES COLLECTED AT DELIVERY FROM A PROSPECTIVE PRE-BIRTH COHORT WITH GENOME-WIDE DNAM PROFILED BY THE ILLUMINA METHYLATIONEPIC ARRAY. WE ESTIMATED PROPORTIONS OF SEVEN COMMON CELL TYPES IN EACH SAMPLE USING A CORD BLOOD-SPECIFIC DNAM REFERENCE PANEL. LEVERAGING A RECENTLY DEVELOPED APPROACH NAMED CELLDMC, WE PERFORMED CELL TYPE-SPECIFIC EWAS TO IDENTIFY CPG LOCI SIGNIFICANTLY ASSOCIATED WITH GDM, OR 3-YEAR-OLD BODY MASS INDEX (BMI) Z-SCORE. A TOTAL OF 1410 CPG LOCI DISPLAYED SIGNIFICANT CELL TYPE-SPECIFIC DIFFERENCES IN METHYLATION LEVEL BETWEEN 23 GDM CASES AND 252 CONTROLS WITH A FALSE DISCOVERY RATE < 0.05. GENE ONTOLOGY ENRICHMENT ANALYSIS INDICATED THAT LDL TRANSPORTATION EMERGED FROM CPG SPECIFICALLY IDENTIFIED FROM B-CELLS DNAM ANALYSES AND THE MITOGEN-ACTIVATED PROTEIN KINASE PATHWAY EMERGED FROM CPG SPECIFICALLY IDENTIFIED FROM NATURAL KILLER CELLS DNAM ANALYSES. IN ADDITION, WE IDENTIFIED FOUR AND SIX LOCI ASSOCIATED WITH 3-YEAR-OLD BMI Z-SCORE THAT WERE SPECIFIC TO CD8+ T-CELLS AND MONOCYTES, RESPECTIVELY. BY PERFORMING GENOME-WIDE PERMUTATION TESTS, WE VALIDATED THAT MOST OF OUR DETECTED SIGNALS HAD LOW FALSE POSITIVE RATES. CONCLUSION: COMPARED TO CONVENTIONAL EWAS ADJUSTING FOR THE EFFECTS OF CELL TYPE HETEROGENEITY, THE PROPOSED APPROACH BASED ON CELL TYPE-SPECIFIC EWAS COULD PROVIDE ADDITIONAL BIOLOGICALLY MEANINGFUL ASSOCIATIONS BETWEEN CPG METHYLATION, PRENATAL MATERNAL GDM OR 3-YEAR-OLD BMI. WITH CAREFUL VALIDATION, THESE FINDINGS MAY PROVIDE NEW INSIGHTS INTO THE PATHOGENESIS, PROGRAMMING, AND CONSEQUENCES OF RELATED CHILDHOOD METABOLIC DYSREGULATION. THEREFORE, WE PROPOSE THAT CELL TYPE-SPECIFIC ANALYSES ARE WORTH CAUTIOUS EXPLORATIONS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
11  3557  39 IMPACT OF BMI AND WAIST CIRCUMFERENCE ON EPIGENOME-WIDE DNA METHYLATION AND IDENTIFICATION OF EPIGENETIC BIOMARKERS IN BLOOD: AN EWAS IN MULTI-ETHNIC ASIAN INDIVIDUALS. BACKGROUND: THE PREVALENCE OF OBESITY AND ITS RELATED CHRONIC DISEASES HAVE BEEN INCREASING ESPECIALLY IN ASIAN COUNTRIES. OBESITY-RELATED GENETIC VARIANTS HAVE BEEN IDENTIFIED, BUT THESE EXPLAIN LITTLE OF THE VARIATION IN BMI. RECENT STUDIES REPORTED ASSOCIATIONS BETWEEN DNA METHYLATION AND OBESITY, MOSTLY IN NON-ASIAN POPULATIONS. METHODS: WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY (EWAS) ON GENERAL ADIPOSITY (BODY MASS INDEX, BMI) AND ABDOMINAL ADIPOSITY (WAIST CIRCUMFERENCE, WC) IN 409 MULTI-ETHNIC ASIAN INDIVIDUALS AND REPLICATED BMI AND WAIST-ASSOCIATED DNA METHYLATION CPGS IDENTIFIED IN OTHER POPULATIONS. THE CROSS-LAGGED PANEL MODEL AND MENDELIAN RANDOMIZATION WERE USED TO ASSESS THE TEMPORAL RELATIONSHIP BETWEEN METHYLATION AND BMI. THE TEMPORAL RELATIONSHIP BETWEEN THE IDENTIFIED CPGS AND INFLAMMATION AND METABOLIC MARKERS WAS ALSO EXAMINED. RESULTS: EWAS IDENTIFIED 116 DNA METHYLATION CPGS INDEPENDENTLY ASSOCIATED WITH BMI AND EIGHT INDEPENDENTLY ASSOCIATED WITH WC AT FALSE DISCOVERY RATE P(FDR) < 0.05 IN 409 ASIAN SAMPLES. WE REPLICATED 110 BMI-ASSOCIATED CPGS PREVIOUSLY REPORTED IN EUROPEANS AND IDENTIFIED SIX NOVEL BMI-ASSOCIATED CPGS AND TWO NOVEL WC-ASSOCIATED CPGS. WE OBSERVED HIGH CONSISTENCY IN ASSOCIATION DIRECTION OF EFFECT COMPARED TO STUDIES IN OTHER POPULATIONS. CAUSAL RELATIONSHIP ANALYSES INDICATED THAT BMI WAS MORE LIKELY TO BE THE CAUSE OF DNA METHYLATION ALTERATION, RATHER THAN THE CONSEQUENCE. THE CAUSAL ANALYSES USING BMI-ASSOCIATED METHYLATION RISK SCORE ALSO SUGGESTED THAT HIGHER LEVELS OF THE INFLAMMATION MARKER IL-6 WERE LIKELY THE CONSEQUENCE OF METHYLATION CHANGE. CONCLUSION: OUR STUDY PROVIDES EVIDENCE OF AN ASSOCIATION BETWEEN OBESITY AND DNA METHYLATION IN MULTI-ETHNIC ASIANS AND SUGGESTS THAT OBESITY CAN DRIVE METHYLATION CHANGE. THE RESULTS ALSO SUGGESTED POSSIBLE CAUSAL INFLUENCE THAT OBESITY-RELATED METHYLATION CHANGES MIGHT HAVE ON INFLAMMATION AND LIPOPROTEIN LEVELS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
12   521  52 ASSOCIATIONS BETWEEN MATERNAL PSYCHOSOCIAL STRESS, DNA METHYLATION, AND NEWBORN BIRTH WEIGHT IDENTIFIED BY INVESTIGATING METHYLATION AT INDIVIDUAL, REGIONAL, AND GENOME LEVELS. STRESS IS KNOWN TO AFFECT HEALTH THROUGHOUT LIFE AND INTO FUTURE GENERATIONS, BUT THE UNDERLYING MOLECULAR MECHANISMS ARE UNKNOWN. WE TESTED THE HYPOTHESIS THAT MATERNAL PSYCHOSOCIAL STRESS INFLUENCES DNA METHYLATION (DNAM), WHICH IN TURN IMPACTS NEWBORN HEALTH OUTCOMES. SPECIFICALLY, WE ANALYZED DNAM AT INDIVIDUAL, REGIONAL, AND GENOME-WIDE LEVELS TO TEST FOR ASSOCIATIONS WITH MATERNAL STRESS AND NEWBORN BIRTH WEIGHT. MATERNAL VENOUS BLOOD AND NEWBORN CORD BLOOD (N = 24 AND 22, RESPECTIVELY) WERE ASSAYED FOR METHYLATION AT APPROXIMATELY 450,000 CPG SITES. METHYLATION WAS ANALYZED BY EXAMINING CPG SITES INDIVIDUALLY IN AN EPIGENOME-WIDE ASSOCIATION STUDY (EWAS), AS REGIONAL GROUPS USING VARIABLY METHYLATED REGION (VMR) ANALYSIS IN MATERNAL BLOOD ONLY, AND THROUGH THE EPIGENOME-WIDE MEASURES USING GENOME-WIDE MEAN METHYLATION (GMM), HORVATH'S EPIGENETIC CLOCK, AND MITOTIC AGE. THESE METHYLATION MEASURES WERE TESTED FOR ASSOCIATION WITH THREE MEASURES OF MATERNAL STRESS (MATERNAL WAR TRAUMA, CHRONIC STRESS, AND EXPERIENCE OF SEXUAL VIOLENCE) AND ONE HEALTH OUTCOME (NEWBORN BIRTH WEIGHT). WE OBSERVED THAT MATERNAL EXPERIENCES OF WAR TRAUMA, CHRONIC STRESS, AND SEXUAL ASSAULT WERE EACH ASSOCIATED WITH DECREASED NEWBORN BIRTH WEIGHT (P < 1.95 X 10(-7) IN ALL CASES). TESTING INDIVIDUAL CPG SITES USING EWAS, WE OBSERVED NO ASSOCIATIONS BETWEEN DNAM AND ANY MEASURE OF MATERNAL STRESS OR NEWBORN BIRTH WEIGHT IN EITHER MATERNAL OR CORD BLOOD, AFTER BONFERRONI MULTIPLE TESTING CORRECTION. HOWEVER, THE TOP-RANKED CPG SITE IN MATERNAL BLOOD THAT ASSOCIATED WITH MATERNAL CHRONIC STRESS AND SEXUAL VIOLENCE BEFORE MULTIPLE TESTING CORRECTION IS LOCATED NEAR THE SPON1 GENE. TESTING AT A REGIONAL LEVEL, WE FOUND INCREASED METHYLATION OF A VMR IN MATERNAL BLOOD NEAR SPON1 THAT WAS ASSOCIATED WITH CHRONIC STRESS AND SEXUAL VIOLENCE AFTER BONFERRONI MULTIPLE TESTING CORRECTION (P = 1.95 X 10(-7) AND 8.3 X 10(-6), RESPECTIVELY). AT THE EPIGENOMIC LEVEL, CORD BLOOD GMM WAS ASSOCIATED WITH SIGNIFICANTLY HIGHER LEVELS OF WAR TRAUMA (P = 0.025) AND WAS SUGGESTIVELY ASSOCIATED WITH SEXUAL VIOLENCE (P = 0.053). THE OTHER TWO EPIGENOME-WIDE MEASURES WERE NOT ASSOCIATED WITH MATERNAL STRESS OR NEWBORN BIRTH WEIGHT IN EITHER TISSUE TYPE. DESPITE OUR SMALL SAMPLE SIZE, WE IDENTIFIED ASSOCIATIONS EVEN AFTER CONSERVATIVE MULTIPLE TESTING CORRECTION. SPECIFICALLY, WE FOUND ASSOCIATIONS BETWEEN DNAM AND THE THREE MEASURES OF MATERNAL STRESS ACROSS BOTH TISSUES; SPECIFICALLY, A VMR IN MATERNAL BLOOD AND GMM IN CORD BLOOD WERE BOTH ASSOCIATED WITH DIFFERENT MEASURES OF MATERNAL STRESS. THE ASSOCIATION OF CORD BLOOD GMM, BUT NOT MATERNAL BLOOD GMM, WITH MATERNAL STRESS MAY SUGGEST DIFFERENT RESPONSES TO STRESS IN MOTHER AND NEWBORN. IT IS NOTEWORTHY THAT WE FOUND ASSOCIATIONS ONLY WHEN CPG SITES WERE ANALYZED IN AGGREGATE, EITHER AS VMRS OR AS A BROAD SUMMARY MEASURE OF GMM.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
13  6761  38 X CHROMOSOME-WIDE ANALYSIS IDENTIFIES DNA METHYLATION SITES INFLUENCED BY CIGARETTE SMOKING. BACKGROUND: TOBACCO SMOKING IS A MAJOR CAUSE OF CHRONIC DISEASE WORLDWIDE. SMOKING MAY INDUCE CELLULAR AND MOLECULAR CHANGES INCLUDING EPIGENETIC MODIFICATION, WITH BOTH SHORT-TERM AND LONG-TERM MODIFICATION PATTERNS THAT MAY CONTRIBUTE TO PHENOTYPIC EXPRESSION OF DISEASES. RECENT EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) HAVE IDENTIFIED DOZENS OF SMOKING-RELATED DNA METHYLATION (DNAM) SITES. HOWEVER, THE X CHROMOSOMAL DNAM SITES HAVE BEEN LARGELY OVERLOOKED DUE TO A LACK OF AN ANALYTICAL FRAMEWORK FOR DEALING WITH THE SEX-DIMORPHIC DISTRIBUTION. TO IDENTIFY NOVEL SMOKING-RELATED DNAM SITES ON THE X CHROMOSOME, WE EXAMINED THE MODALITY OF EACH X CHROMOSOMAL DNAM SITE AND CONDUCTED A SEX-SPECIFIC ASSOCIATION STUDY OF CIGARETTE SMOKING. RESULTS: WE USED A DISCOVERY SAMPLE OF 139 MIDDLE-AGE TWINS, AND THREE REPLICATION SAMPLES OF 78 TWINS, 464 AND 333 UNRELATED INDIVIDUALS INCLUDING 47, 17, 22, AND 89 CURRENT SMOKERS, RESPECTIVELY. AFTER CORRECTION FOR MULTIPLE TESTING, THE TOP SMOKING-RELATED DNAM SITES IN BCOR AND TSC22D3 WERE SIGNIFICANTLY HYPERMETHYLATED AND HYPOMETHYLATED, RESPECTIVELY, AMONG CURRENT SMOKERS. THESE SMOKING-ASSOCIATED SITES WERE REPLICATED WITH META-ANALYSIS P-VALUES OF 9.17 X 10(-12) AND 1.61 X 10(-9). FOR BOTH SITES, THE SMOKING EFFECTS ON METHYLATION LEVELS WERE LARGER IN MALES THAN THAT IN FEMALES. CONCLUSIONS: OUR FINDINGS HIGHLIGHT THE IMPORTANCE OF INVESTIGATING X CHROMOSOME METHYLATION PATTERNS AND THEIR ASSOCIATIONS WITH ENVIRONMENTAL EXPOSURES AND DISEASE PHENOTYPES AND DEMONSTRATE A ROBUST STATISTICAL METHODOLOGY FOR SUCH STUDY. EXISTING EWAS OF HUMAN DISEASES SHOULD INCORPORATE THE X CHROMOSOMAL SITES TO COMPLETE A COMPREHENSIVE EPIGENOME-WIDE SCAN.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
14   972  42 CHRONIC OBSTRUCTIVE PULMONARY DISEASE IS ASSOCIATED WITH EPIGENOME-WIDE DIFFERENTIAL METHYLATION IN BAL LUNG CELLS. DNA METHYLATION PATTERNS IN CHRONIC PULMONARY OBSTRUCTIVE DISEASE (COPD) MIGHT OFFER NEW INSIGHTS INTO DISEASE PATHOGENESIS. TO ASSESS METHYLATION PROFILES IN THE MAIN COPD TARGET ORGAN, WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY ON BAL CELLS. BRONCHOSCOPIES WERE PERFORMED IN 18 SUBJECTS WITH COPD AND 15 CONTROL SUBJECTS (EX- AND CURRENT SMOKERS). DNA METHYLATION WAS MEASURED USING THE ILLUMINA METHYLATIONEPIC BEADCHIP KIT, COVERING MORE THAN 850,000 CPGS. DIFFERENTIALLY METHYLATED POSITIONS (DMPS) WERE EXAMINED FOR 1) ENRICHMENT IN PATHWAYS AND FUNCTIONAL GENE RELATIONSHIPS USING THE KYOTO ENCYCLOPEDIA OF GENES AND GENOMES AND GENE ONTOLOGY, 2) ACCELERATED AGING USING HORVATH'S EPIGENETIC CLOCK, 3) CORRELATION WITH GENE EXPRESSION, AND 4) COLOCALIZATION WITH GENETIC VARIATION. WE FOUND 1,155 BONFERRONI-SIGNIFICANT (P < 6.74 X 10(-8)) DMPS ASSOCIATED WITH COPD, MANY WITH LARGE EFFECT SIZES. FUNCTIONAL ANALYSIS IDENTIFIED BIOLOGICALLY PLAUSIBLE PATHWAYS AND GENE RELATIONSHIPS, INCLUDING ENRICHMENT FOR TRANSCRIPTION FACTOR ACTIVITY. STRONG CORRELATION WAS FOUND BETWEEN DNA METHYLATION AND CHRONOLOGICAL AGE BUT NOT BETWEEN COPD AND ACCELERATED AGING. FOR 79 UNIQUE DMPS, DNA METHYLATION CORRELATED SIGNIFICANTLY WITH GENE EXPRESSION IN BAL CELLS. THIRTY-NINE PERCENT OF DMPS WERE COLOCALIZED WITH COPD-ASSOCIATED SNPS. TO THE BEST OF OUR KNOWLEDGE, THIS IS THE FIRST EPIGENOME-WIDE ASSOCIATION STUDY OF COPD ON BAL CELLS, AND OUR ANALYSES REVEALED MANY DIFFERENTIAL METHYLATION SITES. INTEGRATION WITH MRNA DATA SHOWED A STRONG FUNCTIONAL READOUT FOR RELEVANT GENES, IDENTIFYING SITES WHERE DNA METHYLATION MIGHT DIRECTLY AFFECT EXPRESSION. ALMOST HALF OF DMPS WERE COLOCATED WITH SNPS IDENTIFIED IN PREVIOUS GENOME-WIDE ASSOCIATION STUDIES OF COPD, SUGGESTING JOINT GENETIC AND EPIGENETIC PATHWAYS RELATED TO DISEASE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
15  5744  25 SMOKING-INDUCED EXPRESSION OF THE GPR15 GENE INDICATES ITS POTENTIAL ROLE IN CHRONIC INFLAMMATORY PATHOLOGIES. DESPITE THE DESCRIBED CLEAR EPIGENETIC EFFECTS OF SMOKING, THE EFFECT OF SMOKING ON GENOME-WIDE GENE EXPRESSION IN THE BLOOD IS OBSCURE. WE THEREFORE STUDIED THE SMOKING-INDUCED CHANGES IN THE GENE-EXPRESSION PROFILE OF THE PERIPHERAL BLOOD. RNA WAS EXTRACTED FROM THE WHOLE BLOOD OF 48 INDIVIDUALS WITH A DETAILED SMOKING HISTORY (24 NEVER-SMOKERS, 16 SMOKERS, AND 8 EX-SMOKERS). GENE-EXPRESSION PROFILES WERE EVALUATED WITH RNA SEQUENCING, AND RESULTS WERE ANALYZED SEPARATELY IN 24 MEN AND 24 WOMEN. IN THE MALE SMOKERS, 13 GENES WERE STATISTICALLY SIGNIFICANTLY (FALSE-DISCOVERY RATE <0.1) DIFFERENTIALLY EXPRESSED; IN FEMALE SMOKERS, 5 GENES. ALTHOUGH MOST OF THE DIFFERENTIALLY EXPRESSED GENES WERE DIFFERENT BETWEEN THE MALE AND FEMALE SMOKERS, THE G-PROTEIN-COUPLED RECEPTOR 15 GENE (GPR15) WAS DIFFERENTIALLY EXPRESSED IN BOTH MALE AND FEMALE SMOKERS COMPARED WITH NEVER-SMOKERS. ANALYSIS OF GPR15 METHYLATION IDENTIFIED SIGNIFICANTLY GREATER HYPOMETHYLATION IN SMOKERS COMPARED WITH THAT IN NEVER-SMOKERS. GPR15 IS THE CHEMOATTRACTANT RECEPTOR THAT REGULATES T-CELL MIGRATION AND IMMUNITY. UP-REGULATION OF GPR15 COULD EXPLAIN TO SOME EXTENT THE HEALTH HAZARDS OF SMOKING WITH REGARD TO CHRONIC INFLAMMATORY DISEASES.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
16  2418  33 EPIGENETIC SIGNATURE OF CHRONIC LOW BACK PAIN IN HUMAN T CELLS. OBJECTIVE: DETERMINE IF CHRONIC LOW BACK PAIN (LBP) IS ASSOCIATED WITH DNA METHYLATION SIGNATURES IN HUMAN T CELLS THAT WILL REVEAL NOVEL MECHANISMS AND POTENTIAL THERAPEUTIC TARGETS AND EXPLORE THE FEASIBILITY OF EPIGENETIC DIAGNOSTIC MARKERS FOR PAIN-RELATED PATHOPHYSIOLOGY. METHODS: GENOME-WIDE DNA METHYLATION ANALYSIS OF 850,000 CPG SITES IN WOMEN AND MEN WITH CHRONIC LBP AND PAIN-FREE CONTROLS WAS PERFORMED. T CELLS WERE ISOLATED (DISCOVERY COHORT, N = 32) AND USED TO IDENTIFY DIFFERENTIALLY METHYLATED CPG SITES, AND GENE ONTOLOGIES AND MOLECULAR PATHWAYS WERE IDENTIFIED. A POLYGENIC DNA METHYLATION SCORE FOR LBP WAS GENERATED IN BOTH WOMEN AND MEN. VALIDATION WAS PERFORMED IN AN INDEPENDENT COHORT (VALIDATION COHORT, N = 63) OF CHRONIC LBP AND HEALTHY CONTROLS. RESULTS: ANALYSIS WITH THE DISCOVERY COHORT REVEALED A TOTAL OF 2,496 AND 419 DIFFERENTIALLY METHYLATED CPGS IN WOMEN AND MEN, RESPECTIVELY. IN WOMEN, MOST OF THESE SITES WERE HYPOMETHYLATED AND ENRICHED IN GENES WITH FUNCTIONS IN THE EXTRACELLULAR MATRIX, IN THE IMMUNE SYSTEM (IE, CYTOKINES), OR IN EPIGENETIC PROCESSES. IN MEN, A UNIQUE CHRONIC LBP DNA METHYLATION SIGNATURE WAS IDENTIFIED CHARACTERIZED BY SIGNIFICANT ENRICHMENT FOR GENES FROM THE MAJOR HISTOCOMPATIBILITY COMPLEX. SEX-SPECIFIC POLYGENIC DNA METHYLATION SCORES WERE GENERATED TO ESTIMATE THE PAIN STATUS OF EACH INDIVIDUAL AND CONFIRMED IN THE VALIDATION COHORT USING PYROSEQUENCING. CONCLUSION: THIS STUDY REVEALS SEX-SPECIFIC DNA METHYLATION SIGNATURES IN HUMAN T CELLS THAT DISCRIMINATES CHRONIC LBP PARTICIPANTS FROM HEALTHY CONTROLS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
17  3056  45 GENOME-WIDE DNA METHYLATION ANALYSIS IMPLICATES ENRICHMENT OF INTERFERON PATHWAY IN AFRICAN AMERICAN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND EUROPEAN AMERICANS WITH LUPUS NEPHRITIS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, MULTISYSTEM, INFLAMMATORY AUTOIMMUNE DISEASE THAT DISPROPORTIONATELY AFFECTS WOMEN. TRENDS IN SLE PREVALENCE AND CLINICAL COURSE DIFFER BY ANCESTRY, WITH THOSE OF AFRICAN AMERICAN ANCESTRY PRESENTING WITH MORE ACTIVE, SEVERE AND RAPIDLY PROGRESSIVE DISEASE THAN EUROPEAN AMERICANS. PREVIOUS RESEARCH ESTABLISHED ALTERED EPIGENETIC SIGNATURES IN SLE PATIENTS COMPARED TO CONTROLS. HOWEVER, THE CONTRIBUTION OF ABERRANT DNA METHYLATION (DNAM) TO THE RISK OF SLE BY ANCESTRY AND DIFFERENCES AMONG PATIENTS WITH SLE-ASSOCIATED LUPUS NEPHRITIS (LN) HAS NOT BEEN WELL DESCRIBED. WE EVALUATED THE DNA METHYLOMES OF 87 INDIVIDUALS INCLUDING 41 SLE PATIENTS, WITH AND WITHOUT LN, AND 46 CONTROLS ENROLLED IN AN ANCESTRY DIVERSE, WELL-CHARACTERIZED COHORT STUDY OF ESTABLISHED SLE (41 SLE PATIENTS [20 SLE-LN+, 21 SLE-LN-] AND 46 SEX-, RACE- AND AGE-MATCHED CONTROLS; 55% AFRICAN AMERICAN, 45% EUROPEAN AMERICAN). PARTICIPANTS WERE GENOTYPED USING THE INFINIUM GLOBAL DIVERSITY ARRAY (GDA), AND GENETIC ANCESTRY WAS ESTIMATED USING PRINCIPAL COMPONENTS. GENOME-WIDE DNA METHYLATION WAS INITIALLY MEASURED USING THE ILLUMINA METHYLATIONEPIC 850K BEADCHIP ARRAY FOLLOWED BY METHYLATION-SPECIFIC QPCR TO VALIDATE THE METHYLATION STATUS AT PUTATIVE LOCI. DIFFERENTIALLY METHYLATED POSITIONS (DMP) WERE IDENTIFIED USING A CASE-CONTROL APPROACH ADJUSTED FOR ANCESTRY. WE IDENTIFIED A TOTAL OF 51 DMPS IN CPGS AMONG SLE PATIENTS COMPARED TO CONTROLS. GENES PROXIMAL TO THESE CPGS WERE HIGHLY ENRICHED FOR INVOLVEMENT IN TYPE I INTERFERON SIGNALING. DMPS AMONG EUROPEAN AMERICAN SLE PATIENTS WITH LN WERE SIMILAR TO AFRICAN AMERICAN SLE PATIENTS WITH AND WITHOUT LN. OUR FINDINGS WERE VALIDATED USING AN ORTHOGONAL, METHYL-SPECIFIC PCR FOR THREE SLE-ASSOCIATED DMPS NEAR OR PROXIMAL TO MX1, USP18, AND IFITM1. OUR STUDY CONFIRMS PREVIOUS REPORTS THAT DMPS IN CPGS ASSOCIATED WITH SLE ARE ENRICHED IN TYPE I INTERFERON GENES. HOWEVER, WE SHOW THAT EUROPEAN AMERICAN SLE PATIENTS WITH LN HAVE SIMILAR DNAM PATTERNS TO AFRICAN AMERICAN SLE PATIENTS IRRESPECTIVE OF LN, SUGGESTING THAT ABERRANT DNAM ALTERS ACTIVITY OF TYPE I INTERFERON PATHWAY LEADING TO MORE SEVERE DISEASE INDEPENDENT OF ANCESTRY.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
18  2078  39 EPIGENETIC DIVERGENCE IN THE TRPA1 PROMOTER CORRELATES WITH PRESSURE PAIN THRESHOLDS IN HEALTHY INDIVIDUALS. THE EXPRESSION PATTERN OF IMPORTANT TRANSDUCTION MOLECULES IN NOCICEPTIVE SENSORY NEURONS IS LIKELY TO DICTATE PAIN SENSITIVITY. WHILE THIS NOTION IS WELL ESTABLISHED FOR INCREASED PAIN SENSITIVITIES UNDER CONDITIONS LIKE INFLAMMATION AND NEUROPATHY, LESS IS KNOWN AS TO WHICH MOLECULES ARE DEFINING INTERINDIVIDUAL DIFFERENCES IN PAIN SENSITIVITY IN HEALTHY SUBJECTS. A GENOME-WIDE METHYLATION ANALYSIS ON MONOZYGOTIC TWINS FOUND THAT METHYLATION OF A CPG DINUCLEOTIDE IN THE PROMOTER OF TRANSIENT RECEPTOR POTENTIAL ANKYRIN 1 (TRPA1) IS INVERSELY ASSOCIATED WITH THE THRESHOLD FOR HEAT-INDUCED PAIN. SEVERAL IN VITRO STUDIES ALSO SUGGEST THAT TRPA1 MEDIATES MECHANICAL SENSITIVITY OF SENSORY AFFERENTS, THUS POTENTIALLY MEDIATING PRESSURE-EVOKED PAIN. IN THE PRESENT STUDY, WE THEREFORE INVESTIGATED THE EPIGENETIC PREDISPOSITION FOR PRESSURE PAIN BY ANALYZING THE METHYLATION STATUS OF 47 CPG SITES IN THE PROMOTER REGION OF TRPA1. USING DNA FROM WHOLE-BLOOD SAMPLES OF 75 HEALTHY VOLUNTEERS, WE FOUND THAT THE SAME CPG SITE PREVIOUSLY FOUND TO AFFECT THE THRESHOLD FOR HEAT-EVOKED PAIN IS HYPERMETHYLATED IN SUBJECTS WITH A LOW THRESHOLD FOR PRESSURE PAIN. WE ALSO FOUND GENDER DIFFERENCES, WITH FEMALES DISPLAYING HIGHER METHYLATION RATES COMBINED WITH HIGHER PRESSURE PAIN SENSITIVITIES AS COMPARED WITH MALES. IN CONCLUSION, OUR FINDINGS SUPPORT THE NOTION THAT EPIGENETIC REGULATION OF TRPA1 SEEMS TO REGULATE THERMAL AND MECHANICAL PAIN SENSITIVITIES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
19  5395  47 REDUCED EPIGENETIC AGE IN OLDER ADULTS WITH HIGH SENSE OF PURPOSE IN LIFE. PSYCHOSOCIAL RISK FACTORS HAVE BEEN LINKED WITH ACCELERATED EPIGENETIC AGING, BUT LITTLE IS KNOWN ABOUT WHETHER PSYCHOSOCIAL RESILIENCE FACTORS (EG, SENSE OF PURPOSE IN LIFE) MIGHT REDUCE EPIGENETIC AGE ACCELERATION. IN THIS STUDY, WE TESTED IF OLDER ADULTS WHO EXPERIENCE HIGH LEVELS OF PURPOSE MIGHT SHOW REDUCED EPIGENETIC AGE ACCELERATION. WE EVALUATED THE RELATIONSHIP BETWEEN PURPOSE AND EPIGENETIC AGE ACCELERATION AS MEASURED BY 13 DNA METHYLATION (DNAM) "EPIGENETIC CLOCKS" ASSESSED IN 1 572 OLDER ADULTS FROM THE HEALTH AND RETIREMENT STUDY (MEAN AGE 70 YEARS). WE QUANTIFIED THE TOTAL ASSOCIATION BETWEEN PURPOSE AND DNAM AGE ACCELERATION AS WELL AS THE EXTENT TO WHICH THAT TOTAL ASSOCIATION MIGHT BE ATTRIBUTABLE TO DEMOGRAPHIC FACTORS, CHRONIC DISEASE, OTHER PSYCHOSOCIAL VARIABLES (EG, POSITIVE AFFECT), AND HEALTH-RELATED BEHAVIORS (HEAVY DRINKING, SMOKING, PHYSICAL ACTIVITY, AND BODY MASS INDEX [BMI]). PURPOSE IN LIFE WAS ASSOCIATED WITH REDUCED EPIGENETIC AGE ACCELERATION ACROSS 4 "SECOND-GENERATION" DNAM CLOCKS OPTIMIZED FOR PREDICTING HEALTH AND LONGEVITY (FALSE DISCOVERY RATE [FDR] Q < 0.0001: PHENOAGE, GRIMAGE, ZHANG EPIGENETIC MORTALITY INDEX; FDR Q < 0.05: DUNEDINPOAM). THESE ASSOCIATIONS WERE INDEPENDENT OF DEMOGRAPHIC AND PSYCHOSOCIAL FACTORS, BUT SUBSTANTIALLY ATTENUATED AFTER ADJUSTING FOR HEALTH-RELATED BEHAVIORS (DRINKING, SMOKING, PHYSICAL ACTIVITY, AND BMI). PURPOSE SHOWED NO SIGNIFICANT ASSOCIATION WITH 9 "FIRST-GENERATION" DNAM EPIGENETIC CLOCKS TRAINED ON CHRONOLOGICAL AGE. OLDER ADULTS WITH GREATER PURPOSE IN LIFE SHOW "YOUNGER" DNAM EPIGENETIC AGE ACCELERATION. THESE RESULTS MAY BE DUE IN PART TO ASSOCIATED DIFFERENCES IN HEALTH-RELATED BEHAVIORS. RESULTS SUGGEST NEW OPPORTUNITIES TO REDUCE BIOLOGICAL AGE ACCELERATION BY ENHANCING PURPOSE AND ITS BEHAVIORAL SEQUELAE IN LATE ADULTHOOD.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
20  3063  36 GENOME-WIDE DNA METHYLATION AND LONG-TERM AMBIENT AIR POLLUTION EXPOSURE IN KOREAN ADULTS. BACKGROUND: AMBIENT AIR POLLUTION IS ASSOCIATED WITH NUMEROUS ADVERSE HEALTH OUTCOMES, BUT THE UNDERLYING MECHANISMS ARE NOT WELL UNDERSTOOD; EPIGENETIC EFFECTS INCLUDING ALTERED DNA METHYLATION COULD PLAY A ROLE. TO EVALUATE ASSOCIATIONS OF LONG-TERM AIR POLLUTION EXPOSURE WITH DNA METHYLATION IN BLOOD, WE CONDUCTED AN EPIGENOME-WIDE ASSOCIATION STUDY IN A KOREAN CHRONIC OBSTRUCTIVE PULMONARY DISEASE COHORT (N = 100 INCLUDING 60 CASES) USING ILLUMINA'S INFINIUM HUMANMETHYLATION450K BEADCHIP. ANNUAL AVERAGE CONCENTRATIONS OF PARTICULATE MATTER </= 10 MUM IN DIAMETER (PM(10)) AND NITROGEN DIOXIDE (NO(2)) WERE ESTIMATED AT PARTICIPANTS' RESIDENTIAL ADDRESSES USING EXPOSURE PREDICTION MODELS. WE USED ROBUST LINEAR REGRESSION TO IDENTIFY DIFFERENTIALLY METHYLATED PROBES (DMPS) AND TWO DIFFERENT APPROACHES, DMRCATE AND COMB-P, TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS (DMRS). RESULTS: AFTER MULTIPLE TESTING CORRECTION (FALSE DISCOVERY RATE < 0.05), THERE WERE 12 DMPS AND 27 DMRS ASSOCIATED WITH PM(10) AND 45 DMPS AND 57 DMRS RELATED TO NO(2). DMP CG06992688 (OTUB2) AND SEVERAL DMRS WERE ASSOCIATED WITH BOTH EXPOSURES. ELEVEN DMPS IN RELATION TO NO(2) CONFIRMED PREVIOUS FINDINGS IN EUROPEANS; THE REMAINDER WERE NOVEL. METHYLATION LEVELS OF 39 DMPS WERE ASSOCIATED WITH EXPRESSION LEVELS OF NEARBY GENES IN A SEPARATE DATASET OF 3075 INDIVIDUALS. ENRICHED NETWORKS WERE RELATED TO OUTCOMES ASSOCIATED WITH AIR POLLUTION INCLUDING CARDIOVASCULAR AND RESPIRATORY DISEASES AS WELL AS INFLAMMATORY AND IMMUNE RESPONSES. CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE THAT LONG-TERM AMBIENT AIR POLLUTION EXPOSURE IMPACTS DNA METHYLATION. THE DIFFERENTIAL METHYLATION SIGNALS CAN SERVE AS POTENTIAL AIR POLLUTION BIOMARKERS. THESE RESULTS MAY HELP BETTER UNDERSTAND THE INFLUENCES OF AMBIENT AIR POLLUTION ON HUMAN HEALTH.	2019